Clonal hematopoiesis in monocytes contributes to HIV-associated neuroinflammation

单核细胞的克隆造血作用导致 HIV 相关的神经炎症

基本信息

批准号：
10675693
负责人：
SANJAY B. MAGGIRWAR
金额：
$ 47.26万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675693
关键词：
3-Dimensional Adhesions Affect Anti-HIV Agents Antibodies Blood - brain barrier anatomy Blood Platelets Blood Vessels Blood brain barrier dysfunction Brain Brain Diseases Cell Adhesion Molecules Cell Differentiation process Cells Central Nervous System Characteristics Chronic Circulation Clonal Expansion DNA Methylation DNA Modification Methylases Data Dioxygenases Endothelium Epigenetic Process Event Exhibits Exposure to Extravasation Gene Expression General Population Genes Goals HIV HIV Infections HIV Seronegativity HIV Seropositivity HIV-1 Hematopoiesis Heterogeneity Human Immune Impaired cognition Individual Infiltration Inflammatory Injury Integrins Intercellular adhesion molecule 1 JAK2 gene Learning Literature Macrophage Measures Mediating Modeling Monoclonal Antibodies Mus Myeloid Cells Nervous System Trauma Neurologic Neurologic Symptoms Neuronal Dysfunction P-Selectin P-selectin ligand protein Phenotype Physiological Play Process Promoter Regions Proto-Oncogene Proteins c-myc Role Secondary to Site Sorting Testing Tetanus Helper Peptide Time Vascular Cell Adhesion Molecule-1 Wild Type Mouse antiretroviral therapy astrogliosis axon injury brain endothelial cell cognitive ability demethylation experimental study gene product glial activation improved migration monocyte monolayer mouse model neuroinflammation neuroregulation novel promoter response shear stress

项目摘要

Summary Extravasation of inflammatory monocytes across the blood-brain barrier (BBB) in response to human immunodeficiency virus type-1 (HIV) is a critical event that leads to chronic neuroinflammation, neurologic injury, and subsequent loss of cognitive abilities in a significantly large number of infected individuals. However, given the heterogeneity of monocytes that exists in HIV-infected individuals receiving anti-retroviral therapy (ART), it remains unknown as to whether the neuro-modulatory actions of monocytes are limited to select subset of monocytes. Directly relevant to the goals of RFA-21-250, our supporting data reveals that the ART-treated HIV- infected individuals harbor higher numbers of inflammatory monocytes (CD14lowCD16hi) in their circulation. These cells also exhibit characteristic features of clonal hematopoiesis (CH), such as loss of DNA methyltransferase 3A (DNMT3A) and Tet methylcytosine dioxygenase 2 (TET2) with concurrent increase in the expression of janus kinase-2 (Jak2 ; these three gene products, and few others, are often termed as CH drivers). Interestingly, subsequent experiments in various models suggested that this monocyte subset (1) translocate to the central nervous system (CNS) in response to ART, in platelet-dependent manner, (2) is neuro-modulatory in action, and (3) can be expanded following exposure of monocytes to activated platelets and ART. Based on these findings, we posit that the priming of monocytes by activated platelets potentiates ART-mediated clonal hematopoiesis in monocytes, leading to HIV-associated neurologic injury. In this model, we propose that the composite effect of activated platelets and ART results into clonal expansion of inflammatory (CD14lowCD16hi) monocyte subset with CH, and subsequent demethylation/induction of PSGL-1 gene in them. Functionally, these events facilitate the transmigration of such monocytes into the perivascular spaces within the CNS, where these cells differentiate into macrophage phenotype, while retaining CH profile, and contribute to the neuronal dysfunction. This model then, in full accordance with the available literature, accounts for how neurologic manifestations are initiated and maintained due to immune-CNS interaction in ART-treated HIV- infected individuals.

概括炎症单核细胞响应人类反应而跨过血脑屏障（BBB）外渗 1 型免疫缺陷病毒 (HIV) 是导致慢性神经炎症、神经损伤、以及随后大量感染者丧失认知能力。然而，鉴于接受抗逆转录病毒治疗 (ART) 的 HIV 感染者中存在的单核细胞异质性，目前尚不清楚单核细胞的神经调节作用是否仅限于选定的子集单核细胞。与 RFA-21-250 的目标直接相关，我们的支持数据表明，接受 ART 治疗的 HIV- 感染者的循环系统中含有较多数量的炎症单核细胞 (CD14lowCD16hi)。这些细胞还表现出克隆造血 (CH) 的特征，例如 DNA 丢失甲基转移酶 3A (DNMT3A) 和 Tet 甲基胞嘧啶双加氧酶 2 (TET2) 同时增加 janus 激酶-2（Jak2；这三种基因产物以及其他一些基因产物，通常被称为 CH 驱动程序）的表达。有趣的是，随后在各种模型中进行的实验表明，该单核细胞亚群 (1) 易位至中枢神经系统 (CNS) 以血小板依赖性方式响应 ART，(2) 具有神经调节作用作用，（3）可以在单核细胞暴露于活化的血小板和 ART 后得到扩展。基于这些发现，我们认为活化血小板对单核细胞的启动增强了 ART 介导的单核细胞的克隆性造血，导致 HIV 相关的神经损伤。在这个模型中，我们建议活化血小板和 ART 的复合效应导致炎症细胞克隆扩张 (CD14lowCD16hi) 具有 CH 的单核细胞亚群，以及随后其中 PSGL-1 基因的去甲基化/诱导。从功能上讲，这些事件促进这些单核细胞迁移到血管内的血管周围空间。 CNS，这些细胞分化为巨噬细胞表型，同时保留 CH 特征，并有助于神经元功能障碍。然后，该模型完全按照现有文献，解释了如何在接受 ART 治疗的 HIV 患者中，由于免疫与中枢神经系统的相互作用，神经系统表现得以启动并维持。感染者。